The objective of this application is to better understand the beneficial effects of the mitochondria (mt)-targeted small molecule SS31 and the mt division inhibitor 1 (Mdivi-1) in Alzheimer?s disease (AD) mouse models. Several lines of evidence suggest that age- and amyloid beta (A?)-induced reactive oxygen species (ROS) is associated with mt and synaptic damage in AD. Several studies, including preliminary studies on which the proposed research is in large part based, found that, in postmortem AD brain specimens and brain tissues from AD mice, A? is associated with mt and increased levels of ROS production and mt dysfunction, suggesting that A? may be a key factor in mt dysfunction and neuronal damage. Based on these observations, targeting mt ROS may be an important therapeutic approach to slowing AD progression. However, clinical trials of AD patients to determine the capability of natural antioxidant-based drugs (natural antioxidants, including VitC, VitE, beta-carotene, and melatonin) to slow disease progression yielded limited success. That research did reveal critical information: that natural antioxidants are not capable of crossing the blood brain barrier and are not capable of reaching critical brain areas affected by AD and so cannot protect mt and synapses in those areas. To overcome this challenge, mt-targeted molecule SS31 was developed and has been proven to cross the blood brain barrier in mouse models of neurodegenerative diseases. However, its efficacies have not been studied preclinically in AD mouse models and clinically in AD patients. Further, in other studies of AD disease progression, defective mt dynamics (increased fission and decreased fusion) were found in AD neurons. Results from others and our preliminary studies revealed that the fission protein Drp1 interacts with A? and phosphorylated tau, resulting in excessive mt fragmentation, increased ROS production, defective transport of mt to synapses, low synaptic ATP, and synaptic dysfunction. Preliminary high throughput studies found that mt division inhibitor Mdivi1 reduces excessive mt fragmentation and increases mt fusion in cell models of AD, suggesting that Mdivi1 is a promising drug to treat AD. The objective of our R01 application is to determine protective effects of SS31 (Aim 1), Mdivi-1 (Aim 2), and SS31+Mdivi1 (Aim 3) in APP-KI and tau-Tg mouse models of AD and non-transgenic WT mice, at 2 stages (preventive and curative) of disease progression. Using state-of-the-art methods, mt structural and functional changes, A? and tau pathologies, and synaptic alterations will be studied in SS31-, Mdivi1-, SS31+Mdivi1-treated and untreated APP-KI and tau-Tg mice and non-transgenic WT mice. The outcome of the proposed research will take researchers closer to developing therapeutic approaches capable of slowing AD progression ? and, ultimately, of curing AD.